tbuckley/cabot-search huggingface dataset:
Association of lifestyle-related risk factors with incidence and mortality rates of colorectal cancer among adolescents and young adults (AYA) in the United States.
Authors: Udhayvir Singh Grewal, Manik Aggarwal, Prabhat Kumar, Naomi Fei, Varun Monga, Chandrikha Chandrasekharan
Journal: Journal of Clinical Oncology (2023)

80 Background: Incidence of colorectal cancer (CRC) among adolescents and young adults (AYA) is increasing. A significant proportion of adolescents and young adults (AYA) with colorectal cancer (CRC) lack traceable genetic risk factors. We sought to study the impact of lifestyle-related risk factors on the incidence and mortality of CRC in these patients. Methods: We extracted data on crude incidence and mortality rates of CRC (reported per 100,000 population) for ages 15-39 years in all 50 U.S. states and District of Columbia from the Center for Disease Control (CDC) WONDER database (1999-2018). Data on risk factors such as obesity, physical activity, alcohol and tobacco abuse and nutrition were obtained from the Behavioral Risk Factor Surveillance System (BRFSS, 2020). Correlations were analyzed using Pearson’s co-efficient. p &lt; 0.05 was considered statistically significant. Statistical analysis was performed using VassarStats. Results: Median crude incidence and mortality rates of CRC in AYA in the US from 1999-2018 were 3.8 (IQR 3.2, 4.4) and 0.7 (IQR 0.5,0.9) per 100,000 population respectively. States with higher age-adjusted prevalence of obesity per 100,000 had higher incidence (r = 0.36, p = 0.01) and mortality rates (r = 0.49, p = 0.0002) of CRC in AYA population. States with a higher age-adjusted prevalence of adherence to recommended weekly aerobic activity had lower incidence (r = -0.4515, p = 0.001) and mortality (r = -0.569, p &lt; 0.0001) rates. While states with higher age-adjusted prevalence of tobacco abuse had higher incidence rate of CRC (r = 0.33, p = 0.02), there was no correlation with mortality rates (r = 0.24, p = 0.09). Higher prevalence of alcohol consumption was associated with decreased mortality rate (r = -0.44, p = 0.001), with no impact on incidence rate (r = -0.16, p = 0.26). States with lower daily consumption of fruits had higher incidence (r = 0.37, p = 0.01) and mortality rates (r = 0.59, p &lt; 0.0001). No correlation of daily consumption of vegetables with incidence (r = -0.1516, p = 0.29) and mortality (r = 0.18, p = 0.22) rates was noted. Conclusions: In the current analysis, higher prevalence of obesity, lower rates of aerobic activity and lower daily consumption of fruits were strongly associated with increased incidence and mortality rates. The impact of tobacco abuse and alcohol consumption was more variable. Apart from improving access to genetic testing and counseling, efforts aimed at mitigating the rise of CRC incidence among AYA should also focus on traditional lifestyle-related risk factors.
Phase II trial of second-line regorafenib in patients with unresectable hepatocellular carcinoma after progression on first-line atezolizumab plus bevacizumab: REGONEXT trial.
Authors: Jaekyung Cheon, Baek-Yeol Ryoo, Beodeul Kang, Hongjae Chon, Changhoon Yoo
Journal: Journal of Clinical Oncology (2023)

TPS634 Background: Atezolizumab-bevacizumab (Ate/Bev) has demonstrated efficacy and safety in patients with advanced hepatocellular carcinoma (HCC) in the phase III trial, and is the new standard of care for first-line treatment of advanced HCC. However, the optimal sequence of therapy after failure of Ate/Bev is unknown. Regorafenib is an oral multikinase inhibitor that blocks the activity of protein kinases involved in angiogenesis, oncogenesis, metastasis, and tumour immunity. Although regorafenib showed survival benefit as subsequent treatment in patients with advanced HCC after progression on sorafenib, the efficacy and safety of regorafenib as subsequent therapy after Ate/Bev has not been investigated yet. Therefore, we designed a phase II trial investigating the efficacy and safety of regorafenib as second-line therapy in patients with advanced HCC who progressed on first-line Ate/Bev. Methods: This is a phase II, multicenter, single-arm study in patients with advanced HCC who had progression on first-line Ate/Bev. Additional key eligibility criteria include with Eastern Cooperative Oncology Group performance status 0–1, Child-Pugh score of 5 or 6, evaluable disease per RECIST v1.1, prior administration of at least 2 cycles of Ate/Bev, and adequate organ function. Key exclusion criteria include fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma, prior regorafenib treatment, clinically significant bleeding within 28 days of enrollment and untreated or symptomatic CNS or leptomeningeal metastasis. Eligible patients will receive oral regorafenib 160 mg daily for 3 weeks of every 4-week cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival, time to progression, overall response rate (ORR), disease control rate and safety. ORR and PFS is assessed per RECIST v 1.1. This study is ongoing and 18 of planned 40 patients have been enrolled. This study is prospectively registered at ClinicalTrials.gov, NCT5134532.
Endoscopic resection of gastrointestinal stromal tumor: The role of clip-and-cut endoscopic full-thickness resection.
Authors: Hwoon-Yong Jung
Journal: Journal of Clinical Oncology (2023)

399 Background: To overcome the technical limitations of classic endoscopic resection for gastric gastrointestinal stromal tumors (GISTs), various methods have been developed. We analyzed the results of endoscopic submucosal dissection (ESD) and clip-and-cut endoscopic full-thickness resection (CASE), a modified full-thickness resection method for gastric GISTs to identify the role and its feasibility of CASE. Methods: The medical records of 83 patients diagnosed with GISTs after ER in 2005–2021 were retrospectively reviewed. ESD and CASE were performed in 51 and 32 patients. The clinical characteristics and outcomes were analyzed. Results: The GISTs were mainly found in the upper third of stomach for ESD (52.9%) and CASE (90.6%). In CASE group, there was a tendency that the most of GISTs were in deep muscularis propria or serosal layer (96.9%) compared to ESD group (45.1%). The R0 resection rates were 51.0% in ESD and 84.4% in CASE group, respectively. Perforation during procedure was frequently found in CASE group (25.5% vs. 68.8%), however only three patients were progressed to peritonitis. Seven cases (8.4%) required surgical treatment (6 ESD, 1 CASE) due to residual tumor (n=5), and post-procedure adverse events (n=2). No R0 or R1 resected cases experienced recurrence during the median 14-month follow-up except for one patient in ESD group. Conclusions: CASE showed higher R0 resection rate and was useful and safe in removing small gastric GISTs.
Preliminary results of TQB2450 (PD-L1 blockade) plus anlotinib combined with oxaliplatin and capecitabine in the first-line treatment of advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: A single-arm, multicenter phase II clinical trial.
Authors: Ning Li, Wen-Ying Deng, Yi-Jie Ma, Liang-Yu Bie, Chi Zhang, Chen Wei, Suxia Luo
Journal: Journal of Clinical Oncology (2023)

367 Background: Efficacy and prognosis of chemotherapy in first-line setting for patients (pts) with advanced HER2-negative G/GEJ adenocarcinoma was dismal currently. PD-1 blockades combined with chemotherapy as first-line regimen exhibited superior efficacy for pts with G/GEJ adenocarcinoma recently, and the efficacy of tumor regression still needs to be improved. Anlotinib was a novel oral multi-targeted tyrosine kinase inhibitor for tumor angiogenesis and proliferation, which had been approved for treatment of considerable malignancies in China. We aimed to investigate the efficacy and safety of TQB2450 (PD-L1 blockade) plus anlotinib combined with CAPEOX (oxaliplatin and capecitabine) as first-line regimen for advanced G/GEJ adenocarcinoma and report the preliminary results timely. Methods: Pts with HER2-negative unresectable locally advanced or metastatic G/GEJ adenocarcinoma who did not expose to previous systemic treatment were recruited in this study. Eligible pts received TQB2450 (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1~14, q3w) combined with oxaliplatin (130mg/m 2 , d1, iv, q3w) and capecitabine (1000mg/m 2 , po, bid, d1~14, q3w) for 6 cycles as initial therapy. For those without disease progression (PD), maintenance therapy was adopted with TQB2450 (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1~14, q3w) until PD or unacceptable toxicity. Tumor response was assessed by investigator according to RECIST version 1.1 using CT scans. The calculated sample size was 25. The primary endpoint was ORR, secondary endpoints were DoR, PFS, OS, DCR and safety. Results: From Apr 2021 to Jul 2022, a total of 20 pts were enrolled and available for efficacy evaluation. In best overall response assessment, there were 15 PR (75.0%), 4 SD (20.0%) and 1 NE (5.0%). In consequence, the preliminary ORR was 75.0% (95%CI: 50.9%~91.3%), DCR was 95.0% (95%CI: 75.1%~99.9%). Median PFS of the 20 pts was not yet reached. Furthermore, the most common treatment-emergent adverse events with the incidence &gt;40% were thrombocytopenia (80%), anemia (75%), leukopenia (65%), decreased total protein (45%) and decreased total protein (45%). The common grade ≥3 treatment-emergent adverse events were neutropenia (15%), lymphocyte count decreased (10%), anemia (5%), leukopenia (5%), elevated aspartate aminotransferase (5%) and elevated alkaline phosphatase (5%). Conclusions: Preliminary results suggested that TQB2450 plus anlotinib combined with CAPEOX in first-line setting for advanced G/GEJ adenocarcinoma exhibited encouraging efficacy and manageable adverse events. The conclusion should be validated in more pts consecutively. Clinical trial information: NCT04891900 .
Severe enterocolitis with capecitabine (CAPE) is not a predictor of gastrointestinal (GI) toxicity with infusional 5-fluorouracil (5-FU)–based regimens: An institutional analysis.
Authors: Marie Parish, Ronald Cox, Aditya V. Shreenivas, Amit Mahipal, Sakti Chakrabarti
Journal: Journal of Clinical Oncology (2023)

89 Background: Enterocolitis is a potentially fatal toxicity of CAPE. The safety of infusional 5-FU-based regimens in patients developing severe enterocolitis with CAPE is not well established in the literature. Methods: After institutional review board approval, a database search identified patients who received infusional 5-FU-based regimens between January 2015 and July 2022 in a tertiary care cancer center after experiencing severe CAPE-induced enterocolitis, defined as the presence of grade 3 or higher diarrhea and features of enterocolitis on computed tomography (CT) scan. Data on patient characteristics, grade of CAPE-induced diarrhea, clinical course, details of 5-FU-based regimens administered after recovery, and outcomes were collected by retrospective electronic chart review. Results: Among the 791 patients treated with CAPE during the study period, 27 (3.4%) developed grade 3 or higher diarrhea, and 15 of these 27 patients (1.9%) had evidence of enterocolitis on CT scan. All patients were treated with supportive measures. All but 1 patient recovered fully; 1 patient died due to a condition unrelated to CAPE toxicity. After complete recovery, 7 patients aged 46 to 69 years (median, 68 years) received FOLFOX (oxaliplatin and infusional 5-FU). The time interval between recovery from CAPE-induced enterocolitis and the start of infusional 5-FU ranged from 4 to 20 weeks (median, 12 weeks), with 3 patients starting 5-FU within 4-5 weeks of recovery. Standard dose 5-FU (2400 mg/m2 over 46 hours) was given to 2 of the 7 patients; the remaining 5 patients received 50% to 80% of the standard dose at the beginning of treatment, but eventually tolerated the standard dose. All patients tolerated 5-FU infusion without experiencing any grade 2 or higher 5-FU induced GI toxicity. Conclusions: Most patients developing severe enterocolitis with CAPE recover fully with appropriate supportive measures. Infusional 5-FU-based regimens appear to be safe in this patient group. Severe CAPE-induced enterocolitis should not preclude the use of infusional 5-FU-based regimens, especially in curative-intent settings such as adjuvant therapy.
Synergistic effects of alpelisib (PI3K inhibitor) and ribociclib (CDK4/6 inhibitor) combination in preclinical colorectal cancer models.
Authors: Razia Aslam, Bryan T Hennessy, Sinead Toomey, Catherine Richards
Journal: Journal of Clinical Oncology (2023)

167 Background: Multiple activating genetic mutations in the phosphatidylinositol-3 kinase (PI3K) and the mitogen activated protein kinase (MAPK) pathways have been implicated in the development of resistance to anti-cancer therapies. Ribociclib has limited activity as a single agent in CRC. However, combining Ribociclib with targeted therapies of the MAPK and PI3K pathways may be a promising treatment strategy for CRC. Methods: We explored the in vitro efficacy of drug combinations Ribociclib (R) and Alpelisib (A) in four CRC cell lines with different mutational status; CACO2 ( PIK3CA/KRAS wild-type), LS1034 ( KRAS mutated), SNUC4 ( PIK3CA mutated) and DLD1 ( PIK3CA/KRAS mutated). Drug combination index (CI) was calculated using Calcusyn Biosoft software. We used a western immunoblotting method for protein analysis. The Chick Chorio-Allantoic Membrane (CAM) assay was used for in-vivo analysis of the effect of the drug combination. Results: IC 50 s for R and A were calculated for all four cell lines. CACO2 and DLD1 cells were resistant to Ribociclib (IC 50 &gt; 15µM). The cell lines had varying sensitivity to both drugs. Drug combination analysis showed that the combination of R and A has a synergistic anti-proliferative effect in all CRC cell lines tested. The combination of R and A is highly synergistic in LS1034 cells which harbour a KRAS mutation (CI = 0.16). Relative expression of the proteins Cyclin D1, E2F-1, p-BCL-2, p-AKT, p-Rb and p-S6 was determined by measuring the density of each band from the western blot experiments and normalizing to β-actin. Combined inhibition of CDK4/6 and PI3Kα caused a simultaneous reduction of p-RB, p-AKT and p-S6 and a more complete inhibition of the PI3K/AKT/mTOR pathway in all four cell lines tested. There was also an increase in the expression of the apoptotic marker pBCL2 in cells treated with the combination of R and A compared to vehicle control(VC). We observed a macroscopic reduction of visible tumour in all cell lines treated with the R and A combination in vivo as compared to VC. Microscopic examination also showed less Ki67 staining and negative cytokeratin staining in combination treated groups. Conclusions: We see a synergistic response to treatment with the combination of R and A in all cell lines and this combination may be a rational treatment strategy in colorectal cancer.
Phase Ib of pembrolizumab (pem) in combination with stereotactic body radiotherapy (SBRT) for resectable liver oligometastatic MMR-proficient (pMMR) colorectal cancer (CRC): Final results.
Authors: Dustin A. Deming, Sam Joseph Lubner, Nataliya Volodymyrivna Uboha, Philip Emmerich, Sean Kraus, Noelle K. LoConte, David H. Kim, Kristina A. Matkowskyj, Sharon Weber, Daniel Abbott, Jens C. Eickhoff, Michael F. Bassetti
Journal: Journal of Clinical Oncology (2023)

161 Background: SBRT is a standard treatment option for oligometastatic CRC and is associated with an increase in immunogenic antigen release and influx of immune cells. We hypothesized that radiation would enhance the immunogenicity of pMMR CRC and potentiate the effectiveness of PD-1 blockade. This phase Ib study examined the safety and efficacy of the sequential combination of SBRT and Pem in patients (pts) undergoing resection of their disease. Additionally, the accumulation and proteolysis of versican (VCAN), an immunoregulatory tumor matrix proteoglycan was examined as a novel immunotherapy biomarker. Proteolysis of VCAN results in the release of an immunostimulatory fragment, versikine. Cancers with low VCAN and high versikine (VCAN proteolysis predominant (VPP)) are hypothesized to respond better to immunotherapies. Methods: Eligibility criteria included resectable liver-confined metastatic pMMR CRC. Prior surgery and systemic chemotherapy were allowed. Subjects received sequential SBRT and cycle 1 of Pem prior to operative management and adjuvant Pem. The primary objectives were to determine the safety/tolerability of this regimen and the recurrence free survival (RFS) at 1 year following operative management. Correlative studies examined tumor infiltrating CD8+ T lymphocytes (TILs), VCAN, and versikine using immunohistochemistry. Results: 15 pts (median age 61.5 [range 39-69], 26% female) were enrolled. All pts had prior FOLFOX. The number of liver lesions ranged from 1-6. SBRT median dose was 50 Gy (40-60 Gy) to 1-2 liver lesions. Grade 3/4 AEs included one case of biliary tract injury and biloma, and one case of G3 hypophosphatemia. No grade 3/4 immune-related AEs occurred. All pts completed a minimum follow-up of 1 year post resection (median follow-up 41 months [range 15-64]). In the intention to treat analysis, the 1 year RFS was 67% (historic control 50%), 40% of patients remained cancer free, and 67% of pts are still alive. 2 of 3 pts with BRAF V600E mutations have had early recurrences. 2 pts had VCAN high tumors and both recurred prior to 1 year. 6 pts had VPP cancers and 83% were recurrence free at 1 year and 66% are currently without evidence of cancer. Conclusions: The combination of SBRT with Pem was well tolerated with no signal of increased immunotherapy-related toxicity. This study met its primary endpoint and this regimen deserves further investigation in confirmatory studies. Additionally, VCAN accumulation and proteolysis are promising biomarkers in this setting. Clinical trial information: NCT02837263 .
Two cycles versus four cycles of neoadjuvant camrelizumab plus chemotherapy in patients with locally advanced esophageal squamous cell carcinoma (ESCC): A prospective, multicenter and randomized study.
Authors: Qin Zhang, Guochun Cao, Zhaohui Fan
Journal: Journal of Clinical Oncology (2023)

350 Background: Increasing evidences support the effects of neoadjuvant immune checkpoint inhibitors plus chemotherapy in locally advanced ESCC. However, the period of neoadjuvant is yet to be completely elucidated. This study was designed to compared the efficacy and safety of two cycles with four cycles of neoadjuvant camrelizumab plus chemotherapy in ESCC. Methods: Patients (pts) aged 18 to 75, with pathological confirmed and resectable ESCC were eligible. Enrolled pts were randomly assigned to two or four cycles of neoadjuvant with intravenous camrelizumab (200 mg, day 1) plus albumin-bound paclitaxel (175mg/m2, day 1) and carboplatin (area under curve 5, day 2) of 21-day cycle. The primary endpoint was pathologic complete response (pCR) rate. Secondary endpoints included the R0 resection rate, objective response rate (ORR), disease control rate (DCR) and adverse events (AEs). ChiCTR2100051154. Results: From 1/2022 to 8/2022, 41 pts were enrolled randomized (21 in the two-cycle and 20 in the four-cycle group). There were 15 (71.4%, 15/21) and 6 (30.0%, 6/20) pts underwent surgery. Compared with (46.7%, 7/15) in two-cycle group, we observed a higher pCR rate (50.0%, 3/6) in four-cycle group. The ORR achieved 60% (two-cycle group) and 66.7% (four-cycle group) respectively. DCR and R0 resection rate achieved 100% in both groups. Pts were well-tolerated in both groups, and 4.8% (1/21) and 5.0% (1/20) pts experienced grade 3/4 AEs. Conclusions: It is the first study to compare the periods of immuno-chemotherapy in the neoadjuvant setting for ESCC. Four cycles neoadjuvant achieved a numerically higher pCR rate and ORR compared with two cycles. Moreover, pts in 4-cycle group did not experienced more frequent or serious AEs. Clinical trial information: ChiCTR2100051154 .
Assessment of an emergency 14-day (d) integrative supportive care program (14-EISCP) followed by early chemotherapy (CTx) in symptomatic patients (pts) with advanced pancreatic ductal adenocarcinoma (aPDAC): A prospective ARCAD cohort study.
Authors: Benoit Rousseau, Antoine Falcoz, Clemence Toullec, Thierry Lecomte, Aurélien Lambert, Christophe Tournigand, Veronique Guerin-Meyer, Christophe Louvet, Isabelle Trouilloud, Yves Rinaldi, Romain Coriat, Jerome Dauba, Cindy Neuzillet, Thierry Andre, Jean-Baptiste Bachet, Jerome Cros, Christelle De La Fouchardiere, Marie-Line Garcia-Larnicol, Aimery De Gramont, Pascal Hammel
Journal: Journal of Clinical Oncology (2023)

700 Background: Pts with aPDAC often have general health impairment due to high symptom burden at diagnosis. We investigated prospectively the clinical benefit (CB) of an EISCP followed by CTx as early as suspicion of aPDAC in pts with ECOG performance status (PS)≥2. Methods: In this multicenter study, PS≥2 pts with pathologically confirmed or suspected aPDAC on imaging were included at first oncology visit (V1) in a personalized 14-d EISCP including pain, nutritional, diagnostic/stenting procedures. Post-EISCP PS≤1 pts received mFOLFIRINOX or gemcitabine(Gem)/Nab-paclitaxel(NP), PS≥2 received mFOLFOX7 or investigator choice CTx or best supportive care (BSC). The primary endpoint was the 14-EISCP success on both feasibility of procedures within 14-d±2 and CB defined by post-EISCP PS≤1, ≥5 points improvement of either fatigue/pain/global health EORTC QLQ-C15-PAL quality of life (QOL) scores, or CTx start ≤30d, aiming 59% success for clinical relevance. Secondary endpoint included uni/multivariate median overall survival (mOS) analyses. Results: As of 07/2022, 106 pts were included; 93 pts were evaluable for primary endpoint: male 46%, mean age 74 yrs, PS2/3 79%/21%, metastases (M1) 62%, pathological diagnosis needed 53%, biliary stenting 16%. V1 mean QOL global health score was 48±23. mOS was 4.1 months (IC95 2.8-5.7). The 14-d feasibility was achieved in 71%. Post-EISCP CB was observed in 82% of pts: 13%, PS improvement to 0/1, 23% QOL improvement and/or 73% CTx start ≤30-d. Eight pts (9%) died during the EISCP. The primary endpoint was achieved in 59% of pts (n=55). Overall, 17 pts (16%) received mFOLFIRINOX/GemNP, 32 (30%) FOLFOX, 29 (27%) Gem or 5FU alone, and 28 (27%) BSC. OS analyses are shown. At d30, pts receiving CTx had a mean change of QOL global health score from 51±23 to 60±23. Conclusions: In PS≥2 pts with aPDAC, a personalized 14-EISCP is feasible and lead to a meaningful CB allowing the administration of doublet/triplet CTx in nearly half of the pts. Pts starting CTx within 30d had improved OS. Clinical trial information: NCT02979483 . [Table: see text]